Periodic Reporting for period 1 - HAT-DES (Development of Novel Desaturative Strategies for the Preparation of Aniline Building Blocks via Photoredox-Cobalt–HAT Triple Catalysis)
Berichtszeitraum: 2023-10-01 bis 2025-09-30
The completed work is comprised of two projects, with the aims as outlined herein: (1) devise a strategy to enable controlled oxidative deconstruction of stable aromatic molecules in the presence of more reactive alkenes and, (2) design a metal-free method for the hydrogenation of alkenes which tolerates functional groups usually labile under traditional transition-metal catalysed hydrogenation reactions.
Project 1: Ozonlysis of aromatics in the presence of alkenes
Prior to this work, the controlled oxidative cleavage of aromatic rings represented an attractive, but inherently challenging proposition, because it requires the selective dismantling of a stable aromatic π-system in the presence of more reactive C=C bonds, that are formed after initial dearomatisation. For this reason, the ozonolysis of arenes results in destructive over-oxidation and is not synthetically useful. Other limitations of ozone include poor compatibility with several common functional groups/heterocycles found in pharmaceuticals and safety concerns. This worked seeked to address the fundamental challenge of arene ozonolysis and thereby enable a new mode of fundamental chemical reactivity: achieving chemoselective oxidative cleavage of arenes in the presence of more reactive π-systems (i.e. olefins).
Project 2: Chemoselective photochemical hydrogenation of alkenes using ammonia borane.
The heterogeneous metal-catalysed hydrogenation of alkenes is one of the most robust and important transformations for the generation of valuable chemicals in both industry and academia. However, the selective catalytic hydrogenation of alkenes in the presence of functional groups such as azides, benzyl ethers and epoxides can be challenging. This work aimed to develop of an original gas- and metal-free method for selective hydrogenation of alkenes in the presence of functional groups often incompatible with traditional methods, thereby enabling the selective hydrogenation of olefins in complex molecules.
Project 1: Ozonlysis of aromatics in the presence of alkenes
Prior to this work, the controlled oxidative cleavage of aromatic rings represented an attractive, but inherently challenging proposition, because it requires the selective dismantling of a stable aromatic π-system in the presence of more reactive C=C bonds, that are formed after initial dearomatisation. For this reason, the ozonolysis of arenes results in destructive over-oxidation and is not synthetically useful. Other limitations of ozone include poor compatibility with several common functional groups/heterocycles found in pharmaceuticals and safety concerns. This worked seeked to address the fundamental challenge of arene ozonolysis and thereby enable a new mode of fundamental chemical reactivity: achieving chemoselective oxidative cleavage of arenes in the presence of more reactive π-systems (i.e. olefins).
Project 2: Chemoselective photochemical hydrogenation of alkenes using ammonia borane.
The heterogeneous metal-catalysed hydrogenation of alkenes is one of the most robust and important transformations for the generation of valuable chemicals in both industry and academia. However, the selective catalytic hydrogenation of alkenes in the presence of functional groups such as azides, benzyl ethers and epoxides can be challenging. This work aimed to develop of an original gas- and metal-free method for selective hydrogenation of alkenes in the presence of functional groups often incompatible with traditional methods, thereby enabling the selective hydrogenation of olefins in complex molecules.
Project 1:
This work was published in Science magazine: Science 2025, 387, 1167–1174.
In order to achieve chemoselective oxidative cleavage of arenes in the presence of olefins, it was necessary to devise a new reagent capable of this transformation. Previously (Nature 2022, 610, 810), the group had established that purple light excited nitroarenes were able to oxidatively cleave olefins under mild conditions. While this exact reactivity was undesired in our case, we wondered whether photoexcited nitroarenes could also have a role in oxidatively cleaving other π-systems, such as arenes. Consequently, we screened nitroarenes for their ability to oxidatively cleave arenes and olefins (under identical conditions), and it became evident that nitrobenzene derivatives with lowest-lying π,π* triplet excited-states, where not only competent at effecting the desired arene cleavage reaction, but also exhibited no reactivity toward olefins. Nanosecond transient absorption spectroscopy confirmed that the π,π* triplet excited state of 3,4-dimethoxynitrobenzene is not quenched by olefins (e.g. cyclooctene, styrene), but is strongly quenched by arenes such as 1-methoxynaphthalene. Competition experiments revealed that arenes featuring tethered olefins (terminal, disubstituted, trisubstituted alkenes and styrenes) could be oxidatively cleaved by photoexcited 3,4-dimethoxynitrobenzene with full selectivity. Finally, a scope evaluation determined that electron rich naphthalenes, anisoles, indoles and pyrroles, could be selectively cleaved by this reagent in good yeidls, in the presence of a number of sensitive functional groups, as demonstrated by the late-stage transformations of 10 drug molecules.
Project 2:
We postulated on the basis of pioneering work by Roberts (J. Chem. Soc. Chem. Commun., 1988, 480) that ammonia borane could serve as a solid hydrogen source for radical hydrogenation. Indeed, our optimisation campaign revealed that alkenes (1.0 equiv) in the presence of ammonia borane (1.0 equiv.), a photocatalyst (anthraquinone, 0.2 equiv.), and a thiol precursor (p-tolyl disulfide, 0.1 equiv.) in CHCl3 (0.1 M), with purple light irradiation, were hydrogenated to alkanes in good to excellent yields. Pleasingly, functional groups typically prone to hydrogenolysis or reduction under traditional hydrogenation conditions (e.g. azides, benzyl ethers, epoxides, N-Cbz, nitriles) were tolerated under the reaction conditions, and compatibility with complex molecules was demonstrated by the late-stage hydrogenation of xx molecules. Experimental mechanistic studies and computation indicated the reaction proceeds through a complex mechanism involving HAT with a hydridic B-H of ammonia borane giving a boron-centred radical. This species undergoes XAT with the chloroform solvent (up to 2 times if a subsequent HAT then XAT occurs) delivering ammonia mono- or dichloroborane. These species undergo hydroboration with alkenes, providing B-alkylated ammonia borane species. Finally, H-atom abstraction of an N-H of these species (e.g. by boryl radical), subsequent beta-scission and HAT with the thiol catalyst delivers the final product.
This work was published in Science magazine: Science 2025, 387, 1167–1174.
In order to achieve chemoselective oxidative cleavage of arenes in the presence of olefins, it was necessary to devise a new reagent capable of this transformation. Previously (Nature 2022, 610, 810), the group had established that purple light excited nitroarenes were able to oxidatively cleave olefins under mild conditions. While this exact reactivity was undesired in our case, we wondered whether photoexcited nitroarenes could also have a role in oxidatively cleaving other π-systems, such as arenes. Consequently, we screened nitroarenes for their ability to oxidatively cleave arenes and olefins (under identical conditions), and it became evident that nitrobenzene derivatives with lowest-lying π,π* triplet excited-states, where not only competent at effecting the desired arene cleavage reaction, but also exhibited no reactivity toward olefins. Nanosecond transient absorption spectroscopy confirmed that the π,π* triplet excited state of 3,4-dimethoxynitrobenzene is not quenched by olefins (e.g. cyclooctene, styrene), but is strongly quenched by arenes such as 1-methoxynaphthalene. Competition experiments revealed that arenes featuring tethered olefins (terminal, disubstituted, trisubstituted alkenes and styrenes) could be oxidatively cleaved by photoexcited 3,4-dimethoxynitrobenzene with full selectivity. Finally, a scope evaluation determined that electron rich naphthalenes, anisoles, indoles and pyrroles, could be selectively cleaved by this reagent in good yeidls, in the presence of a number of sensitive functional groups, as demonstrated by the late-stage transformations of 10 drug molecules.
Project 2:
We postulated on the basis of pioneering work by Roberts (J. Chem. Soc. Chem. Commun., 1988, 480) that ammonia borane could serve as a solid hydrogen source for radical hydrogenation. Indeed, our optimisation campaign revealed that alkenes (1.0 equiv) in the presence of ammonia borane (1.0 equiv.), a photocatalyst (anthraquinone, 0.2 equiv.), and a thiol precursor (p-tolyl disulfide, 0.1 equiv.) in CHCl3 (0.1 M), with purple light irradiation, were hydrogenated to alkanes in good to excellent yields. Pleasingly, functional groups typically prone to hydrogenolysis or reduction under traditional hydrogenation conditions (e.g. azides, benzyl ethers, epoxides, N-Cbz, nitriles) were tolerated under the reaction conditions, and compatibility with complex molecules was demonstrated by the late-stage hydrogenation of xx molecules. Experimental mechanistic studies and computation indicated the reaction proceeds through a complex mechanism involving HAT with a hydridic B-H of ammonia borane giving a boron-centred radical. This species undergoes XAT with the chloroform solvent (up to 2 times if a subsequent HAT then XAT occurs) delivering ammonia mono- or dichloroborane. These species undergo hydroboration with alkenes, providing B-alkylated ammonia borane species. Finally, H-atom abstraction of an N-H of these species (e.g. by boryl radical), subsequent beta-scission and HAT with the thiol catalyst delivers the final product.
Project 1:
This is the first and only report that demonstrates that oxidative cleavage of arenes in the presence of more sensitive π-systems can be performed efficiently. Therefore a new reagent has been discovered which allows, for the first time, the controlled non-destructive oxidative cleavage of arenes within complex molecules. This is the first report that shows the excited-state configuration of a class of molecule can be switched in order to provide completely contrasting chemoselectivity.
Project 2:
This report demonstrates that ammonia borane can be utilised to conduct chemoselective hydrogenations of alkenes in complex molecules including functional groups which are typically not to traditional methods. This methodology is metal free and requires only mild photochemical conditions.
This is the first and only report that demonstrates that oxidative cleavage of arenes in the presence of more sensitive π-systems can be performed efficiently. Therefore a new reagent has been discovered which allows, for the first time, the controlled non-destructive oxidative cleavage of arenes within complex molecules. This is the first report that shows the excited-state configuration of a class of molecule can be switched in order to provide completely contrasting chemoselectivity.
Project 2:
This report demonstrates that ammonia borane can be utilised to conduct chemoselective hydrogenations of alkenes in complex molecules including functional groups which are typically not to traditional methods. This methodology is metal free and requires only mild photochemical conditions.